Role of BMP signaling for chondrogenic fate determination in neural crest cells

项目摘要 这是一个国家卫生研究院途径独立奖（K99/R 00）拨款建议，旨在促进职业生涯的 博士Yoshihiro Komatsu博士是密歇根大学牙科学院的研究员， 独立研究立场。候选人是一位训练有素的小鼠发育生物学家， 在颅面发育和早期胚胎发生领域的研究记录， 人类出生缺陷和先天性疾病的病因学。他的目标是获得终身教职 并在颅面骨骼畸形和人类胚胎干细胞领域建立了自己的研究计划， 基于软骨/骨组织再生。 在指导期间（该奖项的K99阶段），候选人将参加高级科学课程 讲习班、职业发展课程、道德培训和负责任地开展研究的教育。他 将在一个丰富的颅面发育生物学的协作环境中工作， 密歇根州，牙科学院，在系主任Paul Krebsbach博士，DDS，博士的指导下， 以及共同导师Yuji Mishina博士和Vesa Kaartinen博士。在K99阶段，候选人将 通过BMP I型受体ACVR 1研究BMP信号传导的作用，以阐明软骨形成细胞的命运 在颅面发育过程中神经嵴细胞的决定。同时，候选人将接受以下培训： 人ES细胞的实验技术及其合理的研究策略。此外该 候选人将增加他的颅面发育的补充分析方法的库存 问题研究这些成就将是通往独立（R 00）阶段的根本桥梁。 在独立（本奖项的R 00阶段），候选人将阐明BMP的作用 调节神经嵴来源的间充质祖细胞中软骨细胞分化的信号传导， 人ES-衍生的间充质干细胞（MSC）。R 00期间的一项拟议研究将侧重于 BMP信号通过ACVR 1在神经嵴源性软骨细胞中调节软骨细胞分化 间充质祖细胞在颅面发育过程中。我们希望发现新的机制， 过量的BMP信号通过ACVR 1导致颅面骨骼畸形。另一 R 00期间的项目将集中在BMP信号如何通过ACVR 1控制的分子机制， 人ES衍生MSC中的软骨细胞分化。我们预计会发现新的信息 BMP信号传导及其在从人ES细胞有效产生软骨细胞中的实际作用。 这项研究具有重大的健康相关性，因为颅面骨骼畸形是其中一个 人类最常见的疾病此外，这项研究直接连接了紧急医疗保健， 需要建立使用人ES细胞产生软骨细胞的策略，因为不止一个 每年有数百万患者接受面部软骨重建相关手术，这是一项昂贵的治疗。

PROJECT SUMMARY This is an NIH Pathway to independence Award (K99/R00) grant proposal, intended to promote the career of Dr. Yoshihiro Komatsu, PhD, a research fellow at the University of Michigan, School of Dentistry, into an independent research position. The Candidate is a trained mouse developmental biologist with a significant track record of research in the fields of craniofacial development and early embryogenesis for addressing the etiology of birth defects and congenital diseases in human. His goal is to secure a tenure-track faculty position and establish his own research program in the field of craniofacial skeletal malformations and human ES cell- based cartilage/bone tissue regeneration. During the mentored (K99 phase in this award), the Candidate will attend advanced scientific workshops, career development sessions, ethics training and education in responsible conduct of research. He will work within a rich and collaborative environment of Craniofacial Developmental Biology at University of Michigan, School of Dentistry, under the mentorship of the Department Chair, Dr. Paul Krebsbach, DDS, PhD, and co-mentors Dr. Yuji Mishina, PhD and Dr. Vesa Kaartinen, PhD. During the K99 phase, the Candidate will study the role of BMP signaling through BMP type I receptor, ACVR1, to elucidate chondrogenic cell fate determination in neural crest cells during craniofacial development. Meanwhile, the Candidate will be trained in the experimental techniques for human ES cells and developing its rational research strategies. In addition, the candidate will increase his inventory of complementary analysis methods for craniofacial developmental studies. These achievements will be the fundamental bridge to an independent (R00) phase. During the independent (R00 phase of this award), the Candidate will elucidate the role of BMP signaling that regulates chondrocyte differentiation in neural crest-derived mesenchymal progenitors and human ES-derived mesenchymal stem cells (MSC). One of the proposed studies during R00 will focus on the regulation of chondrocyte differentiation by BMP signaling through ACVR1 in neural crest-derived mesenchymal progenitors during craniofacial development. We expect to discover novel mechanisms for how an excess amount of BMP signaling through ACVR1 leads to craniofacial skeletal malformation. Another project during R00 will focus on the molecular mechanisms of how BMP signaling through ACVR1 governs the chondrocyte differentiation in human ES-derived MSC. We anticipate uncovering novel information regarding BMP signaling and its practical role in effectively generating chondrocytes from human ES cells. This research has major health relevance, because craniofacial skeletal malformations are one of the most frequent disorders in human. In addition, this research directly connects the urgent health care that is needed to establish the strategies of generating chondrocytes using human ES cells since more than one million patients undergo facial cartilage reconstruction-related procedures every year, a costly treatment.